Pubertal and adult Leydig cell function in Mullerian inhibiting substance-deficient mice

Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both basal and human chorionic gonadotropin (hCG)-stimulated testosterone concentrations were similar. Purified Leydig cells from pubertal MIS-KO mice had lower testosterone but higher androstanediol and androstenedione production rates. In contrast, testosterone, androstanediol, and androstenedione production rates were all lower in adult MIS-KO Leydig cells. Steroidogenic acute regulatory protein expression was lower in pubertal MIS-KO mice compared with WT, whereas 17beta-hydroxy-steroid dehydrogenase and 5alpha-reductase were greater, and P450c17 and P450scc were similar. The expression of steroidogenic acute regulatory protein and 17beta-hydroxysteroid dehydrogenase was lower in adult MIS-KO mice, whereas that of 5alpha-reductase, P450c17, and P450scc was similar. Collectively, these results suggest that in the absence of MIS, Leydig cells remain less differentiated, causing an altered intratesticular androgen milieu that may contribute to the infertility of MIS-KO mice. In immature mice, this deficit in steroidogenic capacity appears to be mediated by a direct loss of MIS action in Leydig cells as well as by indirect effects via the hypothalamic-pituitary-gonadal axis.     

A novel assay to detect nucleotide receptor P2X7 genetic polymorphisms influencing numerous innate immune functions

The importance of accessory signaling pathways amplifying endotoxin responses has recently been highlighted by genetic studies describing LPS-hyporesponsive individuals despite carrying the common allele for TLR4. The nucleotide receptor P2X7 modulates the production of numerous LPS-stimulated inflammatory mediators. We have recently described the largest phenotypic screen known for genetic polymorphisms associated with the nucleotide receptor P2X7, a global regulator of leukocyte function. This required the development of a novel monocyte pore assay with numerous advantages over previous methods and with the potential to facilitate rapid (< 3 h), multiplex analysis of clinical samples. This paper addresses aspects pertinent to the development of the monocyte pore assay, briefly summarizes our results suggesting that P2X7 alleles modulate LPS-stimulated cytokine production, and discusses a model wherein P2X7 may serve as an amplification loop of innate immunity.     

Spectrum and outcome of pancreatic trauma.

BACKGROUND AND AIMS: Pancreatic trauma is associated with high morbidity and mortality. Diagnosis is often difficult and surgery poses a formidable challenge. METHOD: Data from 17 patients of pancreatic trauma gathered from a prospectively maintained database were analysed and the following parameters were considered: mode of injury, diagnostic modalities, associated injury, grade of pancreatic trauma and management. Pancreatic trauma was graded from I through IV, as per Modified Lucas Classification. RESULTS: The median age was 39 years (range 19-61). The aetiology of pancreatic trauma was blunt abdominal trauma in 14 patients and penetrating injury in 3. Associated bowel injury was present in 4 cases (3 penetrating injury and 1 blunt trauma) and 1 case had associated vascular injury. 5 patients had grade I, 3 had grade II, 7 had grade III and 2 had grade IV pancreatic trauma. Contrast enhanced computed tomography scan was used to diagnose pancreatic trauma in all patients with blunt abdominal injury. Immediate diagnosis could be reached in only 4 (28.5%) patients. 7 patients responded to conservative treatment. Of the 10 patients who underwent surgery, 6 required it for the pancreas and the duodenum. (distal pancreatectomy with splenectomy-3, pylorus preserving pancreatoduodenectomy-1, debridement with external drainage-1, associated injuries-duodenum-1). Pancreatic fistula, recurrent pancreatitis and pseudocyst formation were seen in 3 (17.05%), 2 (11.7%) and 1 (5.4%) patient respectively. Death occurred in 4 cases (23.5%), 2 each in grades III and IV pancreatic trauma. CONCLUSIONS: Contrast enhanced computed tomography scan is a useful modality for diagnosing, grading and following up patients with pancreatic trauma. Although a majority of cases with pancreatic trauma respond to conservative treatment, patients with penetrating trauma, and associated bowel injury and higher grade pancreatic trauma require surgical intervention and are also associated with higher morbidity and mortality.